Higher animals including human have approximately 30,000 genes. Among these genes, only about 15% are expressed in each individual. Therefore, every biological phenomenon, such as development, differentiation, homeostasis, response to stimulus, cell cycle regulation, aging and apoptosis (programmed cell death) is determined by what gene is chosen to be expressed (Liang, P. and A. B. Pardee, Science, 257: 967-971, 1992).
The pathological phenomenon such as tumorigenesis is caused by genetic mutation and at last induces changes in gene expression. This kind of genetic change causes abnormality of cell signaling system. Thus, comparison of gene expressions among different cells can be a basic, efficient approach for understanding various biological phenomena. According to the results of previous studies on tumorigenesis, various genetic changes such as loss of chromosomal heterozygosity, activation of oncogenes and inactivation of tumor suppressor genes including p53, are focused on tumor tissues to cause cancer in human (Bishop, J. M., Cell, 64:235-248, 1991, and Hunter, T., Cell, 64:249-270, 1991). 10-30% of cancer is presumably caused by activation of oncogenes resulted from amplification of the oncogenes. The activation of oncogenes becomes an important factor for the studies of etiology of cancer, so that it has been a major target of cancer studies.
Stomach cancer is the most frequent cancer in Asia including Korea and Japan, which has the highest death rate (Parkin et al, Int. J. Cancer 80: 827-841, 1999; Neugut et al, Semin. Oncol. 23: 281-291, 1996). A few genes involved in stomach cancer have been disclosed, so far.
However, it has been recently found out that such genes as p53 (Yokozaki et al, Int. Rev. Cytol. 204: 49-95, 2001), β-catenin (Park, et al, Cancer Res. 59: 4257-4260, 1999), E-cadherin (Berx et al, Hum. Mutat. 12: 226-237, 1998), trefoil factor 1 (Park et al, Gastroenterology 119: 691-698, 2000) and c-met (Lee et al, Oncogene 19: 4947-4953, 2000) demonstrate genetic changes in stomach cancer cases. It was also reported that CA11 (Yoshikawa et al, Jpn. J. Cancer Res. 91: 459-463, 2000; Shiozaki et al, Int. J. Oncol. 19: 701-707, 2001) and TFF1 and TFF2, the trefoil factors synthesized in mucous membrane of stomach (Shiozaki et al, Int. J. Oncol. 19: 701-707, 2001; Kirikoshi and KatohKirikoshi, Int. J. Oncol. 21: 655-659, 2002), were reduced in stomach cancer patients. Hasegawa et al confirmed by cDNA microarray using 23.040 genes expressed in colon type stomach cancer that the expressions of RPL10, HSPCB, LOC56287, IGHM, PGC, REGIA, RNASE1, TFF1 and TFF2 were related to metastasis of stomach cancer (Hasegawa et al, Cancer Res. 62: 7012-7017, 2002). However, diagnosis or treatment of stomach cancer with these genes alone is not enough and a specific target gene of stomach cancer has not been established, yet.
ZNF312b gene is also called as Fezf1 (forebrain embryonic zinc finger-like 1) gene, which was the first identified gene in olfactory sensory neuron (OSN) of the forebrain of Xenopus and has been known to encode a protein having zinc ions (Matsuo-Takasaki et al., Mech. Dev. 93: 201-204, 2000)). This gene is essential for proper termination of the olfactory nerve, formation of olfactory bulb and rostral stream migration of interneuron progenitor and is also an essential factor for cell-autonomously control of axonal projection and olfactory bulb membrane formation control (Tsutomu Hirata et al., Development 133: 1433-1443, 2006). The expression of ZNF312b is observed in the phase of embryo development, but is weak in an adult. The expression of ZNF312b is not observed in other tissues. A few reports about functions of ZNF312b gene have been known, but none of them is related to stomach cancer or cancer development.
The present inventors noticed the increase of the expression of ZNF312b in stomach cancer tissues. Therefore, the present inventors focused our study on the cancer development-related function of ZNF312b gene. As a result, the present inventors completed this invention by confirming that the ZNF312b gene expression was specifically increased in stomach cancer, suggesting that the gene had tumorigenesis related functions, acted as an essential factor for cell proliferation signaling system and increased K-ras expression by binding to the K-ras promoter.